Comparing Statin Drugs

Question:

For the dyslipidemic patient, how do we differentiate between the statins; ie, when should one be used preferentially over the other? Are there significant clinical differences among them?

Statins are widely prescribed for the treatment of dyslipidemia. These drugs are hydroxymethylglutaryl-coenzyme A reductase inhibitors, also known as HMG-CoA reductase inhibitors. They work by reversibly and competitively inhibiting the enzyme necessary for conversion of HMG-CoA to mevalonate, the rate-limiting step in hepatic cholesterol synthesis. This leads to increased low density lipoprotein (LDL)-receptor expression on the hepatocyte surface, increased uptake of LDL, and decreased circulating LDL.^1,2 Statins also decrease triglycerides and modestly increase high density lipoprotein (HDL) levels.

While all statins have the same mechanism of action, they differ in terms of chemistry, pharmacokinetics, potency, cost, and approved indications. The following is a summary of some of the more important distinguishing characteristics.

Chemistry

Lovastatin, pravastatin, and simvastatin are derived from fungi,

whereas atorvastatin, fluvastatin, and rosuvastatin are synthetic.

Atorvastatin, lovastatin, and simvastatin are lipophilic,

whereas pravastatin, rosuvastatin, and fluvastatin are more hydrophilic.

Lipophilic statins cross the blood-brain barrier more readily, which may lead to central nervous system complaints such as insomnia, although this is rare.

Hydrophilic statins exhibit greater hepatoselectivity and less influence on smooth muscle proliferation.^[1,2]

Pharmacokinetics

Lovastatin's absorption increases when taken with food, whereas absorption of atorvastatin, fluvastatin, and pravastatin decreases when taken with food.

Simvastatin and rosuvastatin are not affected by food intake.^[1]

All statins are extensively bound to plasma proteins with the exception of pravastatin, which is about 50% bound to plasma proteins, making it less likely to displace albumin-bound drugs, such as warfarin.^[1,2]

Lovastatin and simvastatin are prodrugs and must be hydrolyzed to the active hydroxy acid, while other statins are administered in the active hydroxy acid form.

All statins are subject to extensive first-pass metabolism with the exception of pravastatin.^[1,2]

important: Neither pravastatin nor rosuvastatin undergo extensive CYP450 metabolism, which can increase a drug's likelihood of producing muscle toxicity due to drug interactions.

Atorvastatin, lovastatin, and simvastatin are metabolized by the 3A4 isoform, while fluvastatin is metabolized by 2C9. Possible drug interactions include 3A4 inhibitors (azole antifungals, macrolides, calcium channel blockers, cyclosporine, cimetidine, and grapefruit juice); 2C9 inhibitors (omeprazole, ritonavir, azole antifungals); and inducers of both 3A4 and 2C9, such as phenobarbital, rifampin, phenytoin, and carbamazepine.^[1,2]

Rosuvastatin, fluvastatin, simvastatin, and pravastatin are eliminated primarily in the feces, whereas atorvastatin and lovastatin are eliminated primarily in the bile. The dosage of pravastatin should be modified in patients with moderate-to-severe renal impairment, and

dosages of lovastatin, rosuvastatin, and simvastatin should be modified in cases of severe renal impairment. No change in dose is needed for atorvastatin or fluvastatin in these patients.^[2]

Due to their longer half-lives, rosuvastatin and atorvastatin can be administered at any time of day. Other statins have shorter half-lives and should be administered in the evening, when synthesis of endogenous cholesterol occurs.

Potency

Rosuvastatin and atorvastain are the most potent statins with respect to lowering LDL, followed by simvastatin and pravastatin. Differences in increasing HDL or decreasing triglycerides are less clear. Doubling a statin dose produces only about a 5% decrease in total cholesterol and a 7% decrease in LDL concentration, so a more potent statin may be necessary in the case of subtherapeutic response.^[3]

Safety

Rare adverse events include liver or skeletal muscle toxicity, and they occur most often when a statin is given in combination with an interacting drug or with another medication that is also hepatotoxic or myotoxic. More common events include gastrointestinal disturbances, headache, insomnia, myalgia, and rash.^[4] Statins are generally well-tolerated, with low dropout rates from clinical trials.^[1]

All statins are in pregnancy category X, defined by the US Food and Drug Administration as contraindicated in pregnancy.

For patients with renal failure, atorvastatin or fluvastatin may be preferred over the others because they are less affected by renal impairment. In clinical situations where patients must receive multiple medications (eg, patients with HIV/AIDS), pravastatin is least likely to interact because it is not metabolized by CYP450.

Cost

Another important distinguishing feature of statins is their cost to the patient. Brand-only statins (atorvastatin, rosuvastatin, fluvastatin) may be too expensive for some patients, may not be in a patient's insurance formulary, or may require a higher co-payment, compared with statins that are available generically (lovastatin, pravastatin, and simvastatin).

Pleiotropic Effects

Statins appear to confer clinical benefits that are independent of their lipid lowering activity; these are known as pleiotropic effects.^[6] Statins inhibit synthesis of nonsteroidal isoprenoid compounds, resulting in improvement of endothelial cell function, modification of inflammatory responses, antioxidant effects, antithrombotic effects, and reduction of smooth muscle proliferation and cholesterol accumulation.^[1,2]While there may be subtle differences among the statins in this regard, the exact clinical relevance of this is uncertain.

Reference:
Darrell Hulisz, PharmD
Associate Professor, Department of Family Medicine, Case Western Reserve University School of Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio


Tests on Rosuvastatin (Crestor)

At 6 weeks, rosuvastatin 10-80 mg reduced LDL cholesterol by a mean of 8.2%, 26%, and 12%-18% more than atorvastatin 10-80 mg, pravastatin 10-40 mg, and simvastatin 10-80 mg, respectively.
MEAN % CHANGE FROM BASELINE IN LDL CHOLESTEROL

Rosuvastatin	Atorvastatin	Simvastatin	Pravastatin
10 mg -45.7%	10 mg -36.8%	10 mg -28.3%	10 mg -20.1%
20 mg -52.4%	20 mg -42.6%	20 mg -35%	20 mg -24.4%
40 mg -55%	40 mg -47,8%	40 mg -38.8%	40 mg -29.7%
80 mg -----	80 mg -51.1%	80 mg -45.8%	----- -----

Mean percent changes in HDL cholesterol in rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol 4.7% to 18.7% more than the comparators. Rosuvastatin also reduced triglycerides significantly more than simvastatin and pravastatin. In addition, National Cholesterol Education Program (NCEP) Adult Treatment Panel III LDL cholesterol goals were achieved by 82% (10 mg) to 89% (both 20 mg and 40 mg) of rosuvastatin patients and 69% (10 mg), 75% (20 mg), 85% (40 mg), and 82% (80 mg) of atorvastatin patients. The difference was not statistically different between atorvastatin and rosuvastatin except for the 20 mg doses (89% and 75%, respectively).

PHARMACOKINETICS (1-2,16-19)

	Rosuvastatin	Atorvastatin	Simvastatin
Absolute bioavailability	20%	12%	< 5%
Protein binding	88%	98%	95%
Volume of distribution	134 L	565 L	---
Metabolism	Minimal hepatic metabolism. The major metabolite is N-desmethyl rosuvastatin (active) via CYP450 2C9. Greater than 90% of activity is due to rosuvastatin. Clearance is not significantly dependent on CYP450 3A4.	Hydrolyzed by liver (CYP450 3A4)	Hydrolyzed by liver (CYP450 3A4)
Excretion	Feces(90%) Urine(10%)	Feces Urine (2%)	Feces(60%) Urine (13%)
Half-life	19 hours	14 hours	---

CONTRAINDICATIONS (1)

Hypersensitivity to any product component.
Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and lactation.

WARNINGS (1)

HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. It is recommended that liver function tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter.
Use with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with rosuvastatin and other drugs in this class.
Use with caution in patients with predisposing factors for myopathy, such as renal impairment, advanced age, and hypothyroidism. Discontinue therapy if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy may be increased with concurrent use of other lipid-lowering therapies or cyclosporine. Combination therapy with rosuvastatin and gemfibrozil should generally be avoided.
The risk of myopathy may be increased in circumstances which increase rosuvastatin drug levels.
Therapy should be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

INITIAL DOSE

For hypercholesterolemia and mixed dyslipidemia, 10 mg orally once daily. Consider 5 mg orally once daily for patients requiring less aggressive LDL-C reductions or who are at risk for myopathy. Consider 20 mg orally once daily for patients with marked hypercholesterolemia (LDL-C > 190 mg/dL). For homozygous familial hypercholesterolemia, 20 mg orally once daily.

DOSE ADJUSTMENT
After initiation, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly. For patients with creatinine clearance < 30 mL/min/1.73 m(2) not on hemodialysis, the starting dose should be 5 mg once daily and not to exceed 10 mg once daily. When used in combination with gemfibrozil, the dose should not exceed 10 mg once daily. When used in combination with cyclosporine, the dose should not exceed 5 mg once daily.
The use of 80 mg was stopped due to rhabdomyolysis and renal impairment during trials. The myotoxic potential (myopathy) of rosuvastatin 10 mg to 40 mg is similar to other statins. Recommendations for liver function test monitoring are similar with most other statins. Due to concerns regarding renal toxicity (proteinuria), the manufacturer will conduct postmarketing surveillance to assess any link between rosuvastatin and kidney problems. Additional studies include an atherosclerosis regression trial, an intervascular ultrasound study, outcome studies, a study in patients with renal failure on dialysis, and a study in patients with elevated C-reactive protein.

Antibiotics and Statins

Some antibiotics, including erythromycin, clarithromycin, itraconazole, ketoconazole and miconazole, can increase your risk of muscle damage if taken with atorvastatin or simvastatin.

Speak to your doctor if you are taking atorvastatin or simvastatin and need to take one of these antibiotics. Your doctor may advise you to stop taking atorvastatin or simvastatin or take a lower dose of the statin while you are on the course of antibiotics.

The antibiotic daptomycin should also not be taken in combination with any statin.

Source: NHS